Characterization of GPR101 Expression Across Different Species

Background: We recently showed that Xq26.3 microduplications are associated with early childhood-onset gigantism, a condition we named X-linked acrogigantism (X-LAG). Patients with X-LAG present with mixed GH/PRL secreting pituitary macroadenomas and/or hyperplasia. The smallest region of overlap for the microduplications include 4 coding genes, of which only one, an orphan G protein coupled receptor named GPR101, is highly expressed in tumor tissue. So far, very little is known regarding GPR101’s exact localization or expression, particularly in humans. Aim of the study: To study GPR101 expression across different species, with a particular focus on the hypothalamus and pituitary gland. Patients and methods: GPR101 expression was investigated at the mRNA and protein level, by qRT-PCR/whole in situ hybridization and immunostaining, respectively, in human, rat, rhesus monkey, and zebrafish tissues. Results:GPR101 was found to be expressed at very low levels or was not expressed in almost all adult human tissues examined, with the exception of specific regions of the brain, including the nucleus accumbens. High expression of GPR101 was observed in the human fetal pituitary but not in adult pituitary tissue and in pituitary tumors other than those with Xq26.3 defect. In contrast to human tissues, adult pituitaries of both rhesus monkey and rat express GPR101. However, the pituitary cell type expressing this receptor differs: gonadotrophs in monkeys and somatotrophs in rats express GPR101. In the developing zebrafish embryo, GPR101 showed a bimodal expression pattern: expression levels progressively waning during the first cell divisions (presumably representing maternal transcripts) and then gradually rising with the appearance of the first somites. Beginning at 48h post-fertilization a strong and brain-specific staining including part of the hypothalamus and pituitary was seen. Conclusions: This study shows that the brain is the major site of GPR101 expression across different species, although divergent species-specific expression patterns are evident, especially concerning the pituitary. These findings suggest that the receptor may play an important role in both brain and pituitary development (zebrafish and human data), and that its expression in the pituitary is regulated in a cell type- and developmental stage-specific manner in different species (rat, monkey, and human data). These differences might reflect the very different growth, development and maturation patterns among species. It is also interesting to note that the highest GPR101 expression levels in adult human tissues were observed in the nucleus accumbens, which plays an important role as the reward center, hinting that GPR101 might also be involved in the regulation of behavior, such as food seeking.